PROJECT SUMMARY/ABSTRACT Most children treated for cancer in the US will achieve long-term survival, and survivorship presents unique challenges for this growing population. Brain tumor survivors are at particular risk for a range of functional impairments, including cognitive, educational, and social difficulties. Cranial radiation therapy is an essential lifesaving treatment but is associated with cognitive decline. Proton beam radiation therapy (PBRT) is one of the most promising recent advances in pediatric brain tumor treatment. The proposed medical advantage of PBRT lies in the precision of radiation delivery with proton beams, depositing maximum dose to clinical targets while minimizing radiation to surrounding tissues. By eliminating unnecessary radiation to surrounding healthy brain tissue, PBRT may spare cognitive functioning better than conventional photon or x-ray irradiation (XRT). Using volumetrics and diffusion tensor imaging (DTI), we will examine associations between white matter (WM) toxicity and neurocognitive outcomes in pediatric brain tumor patients treated with PBRT. Study 1 is a prospective, longitudinal study of WM change and associated neurocognitive outcomes in pediatric brain tumor patients treated with PBRT vs. Surgery Only followed from diagnosis through Early Survivorship. Specific aims include: (1) to compare change in WM volume/integrity over time by treatment group (PBRT vs. Surgery Only and vs. healthy controls (HCs)), and (2) to examine associations between WM toxicity and neurocognitive test scores over time. Study 2 is a cross-sectional study of associations between WM and neurocognitive outcomes during Intermediate Survivorship for pediatric brain tumor survivors treated with PBRT vs. Surgery Only with the following specific aims: (1) to compare WM volume/integrity in survivors by treatment type (PBRT vs. Surgery Only and vs. HCs), and (2) to examine associations between WM toxicity and neurocognitive test scores. Study 3 is a cross-sectional study of WM associations with neurocognitive outcomes during Late Survivorship for pediatric brain tumor survivors treated with PBRT vs. XRT including the following specific aims: (1) to compare WM volume/integrity in survivors by treatment group (PBRT vs. XRT and vs. HCs), and (2) to examine associations between WM toxicity and neurocognitive test scores. This proposal is consistent with NCI's objective to ?reduce the long-term adverse effects of cancer and its treatment? in children and to ?improve the quality of life for cancer patients, survivors, and their families.? Neurocognitive late effects lead to significant educational, social, and occupational limitations for many survivors, greatly affecting their quality of life and functional independence long-term. Research is needed to determine which treatments are best able to limit the suffering associated with post-treatment neurocognitive decline. Our results will have clinical value, providing a timely report of WM correlates of neurocognitive functioning and comparison between treatment modalities.